Background: Psychotic disorders, such as schizophrenia, cause severe impairment and account for 10% of disease burden attributable to mental health causes in the United States. As individuals with psychotic disorders age, they are at high risk for premature cognitive decline, physical impairment, and worsening psychosis, especially in APOE4 allele carriers. This pattern is consistent with Alzheimer's disease or a related dementia (ADRD). Elevated levels of neuroinflammation and tau accumulation have been reported in psychotic disorders, but prior research has been limited by small sample sizes. The proposed project will be the first adequately powered study to evaluate the connection between psychotic disorders and ADRD using plasma markers. Methods: This proposal builds on the parent study (MH094398) that investigates potential accelerated aging in psychotic disorders by characterizing changes in health and functioning over time. Participants with psychotic disorders and healthy controls come from the Suffolk County Mental Health Project (SCMHP; R01 MH110434), the longest running first-episode psychosis study in the world. We have had incredibly consistent participation from this population. We will use generalized linear modeling (GLM) to examine plasma markers as a function of APOE genotype and group (case vs control). We also will investigate symptoms, physical and cognitive impairments as a function of plasma markers. Impact: If funded, this would be the largest study of plasma markers of ADRD in aging individuals with psychotic disorders. Likewise it will be the largest study of neuroinflammation in this population. The proposed study addresses the NIH/NIA's strategic goal to better understand the dynamics of aging with a focus on outlining the geoscientific underpinnings of a lifelong process linking psychosis to early aging and dementia (Goal A). It will produce key evidence regarding hypothesized involvement of tau accumulation in these declining outcomes. Furthermore, we plan to continue following the SCMHP cohort, which will allow us to investigate the role of neurodegeneration biomarkers in psychotic disorders longitudinally. This work may identify opportunities for secondary prevention of poor outcomes in psychotic disorders and may help to define a new category of ADRD. Conclusion: The ultimate goal of this study is to understand why psychotic disorders manifest more rapid onset of aging-related conditions (parent R01). Neuroinflammation may help explain why participants with psychotic disorders are experiencing increased risk of cognitive decay, physical functional limitations, and mortality at such early ages. Crucially, microglial activation is thought to occur early in this population and may cause a neuropathological cascade that parallels ADRD but converts quickly to tauopathy.